Multiple myeloma is incurable hematologic malignancy with an expected median survival of 7-8 years. The proteasome inhibitors, bortezomib, carfilzomib and the recently approved ixazomib, are a mainstay of current myeloma treatment. Despite an initial response rate approaching 90% to proteasome inhibitor-containing combinations, all patients relapse and eventually become resistant to any treatments. We have discovered a distinct proteasome inhibitor, LU-102, which re-sensitizes bortezomib and carfilzomib-resistant cell lines and primary cells from myeloma patients to these FDA-approved proteasome inhibitors, and sensitizes myeloma to sub-toxic doses of carfilzomib in mice. The primary targets of all FDA-approved inhibitors are the 5 sites (PSMB5 and PSMB8) of the proteasome. The primary targets of LU-102 are PSMB7 (2) and PSMB10 (2i) subunits. Thus, we hypothesize that PSMB7 and PSMB10 are novel targets in relapsed and refractory myeloma. LU-102 is protected by two patents, which Dartmouth owns and agreed to license to InhiProt. The specific aim of the phase I of the project is to improve potency and pharmacological properties of LU-102. We will use standard medicinal chemistry approaches to achieve the milestone of developing a new highly specific compound, which specifically inhibits PSMB7 and PSMB10 in bone marrow by >75% at 10 mg/kg, and does not cross blood-brain barrier. In the phase II of the award, we will conduct efficacy experiments in animal models of multiple myeloma, and perform PK and ADMET studies. We will test whether the lead synergizes with other anti-myeloma agents. We will solve structures of new inhibitor in complex with the proteasome, and will use it to refine the lead.